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To assess changes in health-related quality of life (HRQoL) in DISCOVER, a 3-year, longitudinal, observational study of patients with type 2 diabetes initiating a second-line glucose-lowering therapy.HRQoL was assessed using the physical and mental component summary (PCS and MCS) scores of the 36-item Short-Form Health Survey version 2 (score ranges: 0-100; higher denotes better HRQoL) and the Hypoglycaemia Fear Survey II (HFS-II; score range: 0-132 scale; higher indicates greater fear of hypoglycaemia). Latent class growth modelling (LCGM) was used to identify patients with similar score trajectories.Mean baseline PCS (n = 7428), MCS (n = 7453), and HFS-II (n = 5005) scores were 48.0, 45.4, and 15.4, respectively, and remained stable during follow-up. LCGM revealed subgroups with low or decreasing HRQoL. Patients in these subgroups tended to be older, had more comorbidities, and a lower socioeconomic status than in other subgroups. Use of insulin and sulfonylureas was highest in the subgroup with the highest fear of hypoglycaemia.Overall, HRQoL remained stable in DISCOVER patients during follow-up. However, LCGM suggests that some patient characteristics and use of sulfonylureas or insulin are associated with low or decreasing HRQoL, potentially warranting the use of alternative therapies.

Aim To investigate factors associated with health-related quality of life (HRQoL) in patients with type 2 diabetes mellitus (T2D) at initiation of second-line glucose-lowering therapy. Methods DISCOVER is a 3-year, prospective observational study of patients with T2D initiating second-line glucose-lowering therapy, conducted in 38 countries. HRQoL at baseline was assessed using the physical and mental component summary (PCS; MCS) scores of the 36-Item Short Form Health Survey version 2 (SF-36v2) in 31 countries (n = 8309) and the Hypoglycaemia Fear Survey-II (HFS-II) in 23 countries (n = 6516). Factors associated with differences in HRQoL were assessed using multivariable hierarchical regression models. Results Mean PCS and MCS scores were 48.0 (standard deviation [SD]: 7.8) and 45.5 (SD: 10.4), respectively. Factors associated with significantly lower SF-36v2 scores included being female, having a history of macrovascular complications and first-line treatment with oral combinations (vs metformin monotherapy). Mean HFS-II behaviour and worry scores were 8.2 (SD: 9.9) and 7.3 (SD: 11.8), respectively. Increased fear of hypoglycaemia was significantly associated with lower SF-36v2 scores. Conclusions Several patient-, disease- and treatment-related characteristics correlated with HRQoL, indicating that a multifactorial approach is needed to maintain HRQoL in patients with T2D.

Using data from DISCOVER (NCT02322762; NCT02226822), a 3-year, global, observational study programme of patients with type 2 diabetes initiating second-line glucose-lowering therapy, we assessed socioeconomic factors associated with hypoglycaemic events and fear of hypoglycaemia.Data were collected at baseline (second-line therapy initiation) and 6, 12 and 24 months. Factors associated with experiencing a hypoglycaemic event at baseline or during follow-up were determined using a hierarchical logistic regression model and an interval-censored survival analysis, respectively. Fear of hypoglycaemia was assessed using the hypoglycaemia fear survey-II (HFS-II).The overall proportion of patients reporting hypoglycaemic events during follow-up was 7.3%; this was higher in middle-income countries than in high-income countries (8.4% vs 5.8%, p 0.001). Factors associated with an increased risk of hypoglycaemia during follow-up included living in a country with a low gross national income, use of glucose-monitoring equipment and second-line treatment with insulin, meglitinides or sulphonylureas (versus metformin). Experiencing hypoglycaemia was associated with increased HFS-II worry and overall scores.Our results highlight the global inequity in the treatment of type 2 diabetes. Increased risk of hypoglycaemia in middle-income countries may be explained by limited treatment options and may be underestimated because of limited access to glucose-monitoring equipment.

The aim of this study was to define the relationship between time in range (TIR) and hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM).The glycemic profile of 999 Japanese patients was analyzed with FreeStyle Libre Pro Continuous Glucose Monitoring (FLP-CGM) while they continued their prescribed glucose-lowering medications. FLP-CGM data recorded over 8 consecutive days were analyzed.The regression model for HbA1c on TIR was HbA1c = 9.4966-0.0309 × TIR. The predicted HbA1c level for TIR of 70% was 7.33% and is higher than reports subjecting mostly T1DM. The TIR corresponding to HbA1c 7.0% was 80.64%. The patients with low TIR tended to have long duration of diabetes, used high dose of daily insulin, high body mass index, high HbA1c, liver dysfunction and high triglyceride. Relatively higher percentages of patients of this group used sulfonylureas, glucagon like peptide-1 receptor agonists and insulin.Our data showed predicted HbA1c corresponding to TIR is largely depends on study population, thus is not uniform. Our results provide new insights on the management of T2DM. However, caution should be exercised in extending the HbA1C-TIR relationship using FLP-CGM to any other sensors since there could be a risk of hypoglycemia in doing so.

Aims Olfactory dysfunction is associated with the transition from normal cognition to dementia in persons without type 2 diabetes. This study aimed to investigate whether olfactory dysfunction could be an early marker of future dementia in older patients with type 2 diabetes. Methods This exploratory study included 151 older Japanese outpatients with type 2 diabetes who did not have a diagnosis of probable dementia at baseline. A multivariate logistic regression model was used to determine whether Open Essence (OE) test score at baseline is associated with the development of probable dementia. Results Over 3 years, approximately 9% of the study subjects developed probable dementia. Subjects with olfactory dysfunction at baseline developed probable dementia more frequently than those without. Multivariate logistic regression showed that lower OE test score, higher age, lower Mini-Mental State Examination (MMSE) score, higher total protein concentration, and more frequent use of a sulfonylurea are significantly associated with the development of probable dementia. Stepwise multivariate regression analysis demonstrated that change in OE test score over 3 years is significantly associated with change in MMSE score. Conclusions Our study suggested that olfactory dysfunction precedes the development of probable dementia in older patients with type 2 diabetes.

To compare the efficacy on glycemic parameters between a 12-week administration of once-daily linagliptin and thrice-daily voglibose in Japanese patients with type 2 diabetes.In a multi-center, randomized, parallel-group study, 382 patients with diabetes were randomized to the linagliptin group (n=192) or the voglibose group (n=190). A meal tolerance test was performed at weeks 0 and 12. Primary outcomes were the change from baseline to week 12 in serum glucose levels at 2h during the meal tolerance test, HbA1c levels, and serum fasting glucose levels, which were compared between the 2 groups.Whereas changes in serum glucose levels at 2h during the meal tolerance test did not differ between the groups, the mean change in HbA1c levels from baseline to week 12 in the linagliptin group (-0.5±0.5% [-5.1±5.4mmol/mol]) was significantly larger than in the voglibose group (-0.2±0.5% [-2.7±5.4mmol/mol]). In addition, there was significant difference in changes in serum fasting glucose levels (-0.51±0.95mmol/L in the linagliptin group vs. -0.18±0.92mmol/L in the voglibose group, P0.001). The incidences of hypoglycemia, serious adverse events (AEs), and discontinuations due to AEs were low and similar in both groups. However, gastrointestinal AEs were significantly lower in the linagliptin group (1.05% vs. 5.85%; P=0.01).These data suggested that linagliptin monotherapy had a stronger glucose-lowering effect than voglibose monotherapy with respect to HbA1c and serum fasting glucose levels, but not serum glucose levels 2h after the start of the meal tolerance test.

Aims Recent clinical studies identified the relation between olfactory dysfunction and cognitive impairment in the elderly without type 2 diabetes mellitus. The aim of the present study was to define the relation between olfactory function and cognition in elderly patients with type 2 diabetes mellitus. Methods The study participants comprised 250 elderly (age, 68–77, median 72) Japanese outpatient with type 2 diabetes mellitus free of clinically-evident cognitive impairment. Olfactory and cognitive functions were evaluated by the Open Essence (OE) test and Mini-mental State Examination (MMSE), respectively. Results Based on the MMSE score, 62.0%, 24.4%, and 13.6% of the participants were considered to have no impairment, possible cognitive impairment and probable dementia, respectively. The OE test score of the probable dementia group was significantly lower than other groups. Furthermore, age and serum uric acid were significantly higher in the probable dementia group than other groups. Simple correlation analysis showed positive correlation between the MMSE score and diastolic blood pressure, education, OE test score, total cholesterol, LDL cholesterol, folic acid, and negative correlation with age, HbA 1c , aspartate aminotransferase, serum adiponectin and urinary albumin excretion. Multivariate regression analysis showed that OE test score correlated significantly and independently with MMSE score (standardized coefficients β = 0.542, R 2 = 0.478, P Conclusions The results suggested the association of olfactory dysfunction with cognitive impairment in elderly patients with type 2 diabetes mellitus.

The aim of this retrospective study was to investigate the relationship between progression of carotid intima-media thickness (cIMT) and cardiovascular events in Japanese patients with type 2 diabetes mellitus (T2DM) and free of history of cardiovascular events.Patients with T2DM (n=342) without history of cardiovascular events whose cIMT was assessed more than twice by ultrasonography were recruited and followed up for cardiovascular events.During a mean follow-up of 7.6 years, 56 (16.4%) cardiovascular events (27 coronary events and 29 cerebrovascular events) were recorded. Multivariate analysis with the Cox proportional hazard model identified cIMT progression as a significant determinant of cardiovascular events, with a hazard ratio (HR) of 2.24 (95% confidence interval; CI, 1.25-4.03, P0.01), in addition to baseline cIMT. The Kaplan-Meier curves also showed significantly higher event rate in patients with high cIMT progression compared with those with low cIMT progression (log-rank χ(2)=6.65; P0.01). Furthermore, the combination of high baseline cIMT and high cIMT progression was a significant predictor of cardiovascular events.Our findings suggest that cIMT progression, in addition to baseline cIMT, is a predictor of cardiovascular events in patients with T2DM without history of cardiovascular events, and that the combination of cIMT progression and baseline cIMT has a strong predictive power for such events.

It is likely that the C allele of the polymorphism at position 29 of the translated sequence of transforming growth factor (TGF)-β1 gene, which codes a pleiotropic cytokine expressed in a variety of cells, is a susceptibility allele for cerebral infarction in Japanese type 2 diabetic patients.

To our knowledge, there is currently no insulin infusion protocol for critically ill patients especially designed for Asian diabetics although many such protocols are used in Western countries. In this study, we modified the Yale insulin infusion protocol taking into consideration the characteristics of Japanese diabetics and hospital environment. We tested the modified protocol in 40 type 2 diabetic patients after elective open-heart surgery (MY group) comparing with 35 type 2 diabetic patients under empirical blood glucose control (EC group). Analyses of 1656 blood glucose measurements during insulin infusion revealed that percentage of samples that showed achievement of target blood glucose level (80-140 mg/dl) was higher under MY (78+/-15%, n=870) than EC (57+/-23%, n=786, p0.0001). On the other hand, the percentage of samples in which blood glucose was less than 60 mg/dl was comparable in the two groups (MY: 0.5+/-5.9 per thousand, EC: 5.1+/-18.5 per thousand). None of the patients with hypoglycemia showed significant clinical adverse effects. In conclusion, our modified Yale insulin infusion protocol is effective and safe for tight blood glucose control in Japanese diabetic patients after open-heart surgery.

Oxidative stress is induced under diabetic conditions and causes various forms of tissue damage in patients with diabetes. Recently, pancreatic beta-cells have emerged as a putative target of oxidative stress-induced tissue damage and this seems to explain in part the progressive deterioration of beta-cell function in type 2 diabetes. As a step toward clinical trial of antioxidant for type 2 diabetes, we investigated the possible anti-diabetic effects of probucol, an antioxidant widely used as an anti-hyperlipidemic agent, on preservation of beta-cell function in diabetic C57BL/KsJ-db/db mice. Probucol-containing diet was given to mice from 6 to 16 weeks of age. Immunostaining for oxidative stress markers such as 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1 revealed that probucol treatment decreased reactive oxygen species (ROS) in pancreatic islets of diabetic animals. Oxidative stress is known to enhance apoptosis of beta-cells and to suppress insulin biosynthesis, but probucol treatment led to preservation of beta-cell mass and the insulin content. According to intraperitoneal glucose tolerance tests, the probucol treatment preserved glucose-stimulated insulin secretion and improved glucose tolerance at 10 and 16 weeks: insulin, 280+/-82 vs. 914+/-238 pmol/l (120 min, at 16 weeks; P

Intensive insulin therapy composed of bolus and basal insulin has been believed as the most powerful recipe for glycemic control of both type 1 and type 2 diabetes. In this study, we investigated the effects of changes in basal/total daily insulin ratio (B/TD ratio) in type 2 diabetes patients on intensive insulin therapy including insulin glargine. The B/TD ratio used in our Japanese patients was about 0.35, and the ratio was increased up to about 0.46+/-0.12 without change of total insulin daily dose. After 24-week-treatment, mean glycated albumin of the patients whose B/TD ratio was increased was significantly lower than those of the patients whose B/TD ratio was not changed. Our results suggest that adequate supplementation of basal insulin may be important for maximum effect of bolus insulin even in Japanese who have serious defect in postprandial rapid insulin secretion.

We document the first reported case of attempted suicide with the GLP-1 receptor agonist, liraglutide. A 33-year-old Japanese woman with type 2 diabetes reported subcutaneously injected 72 mg of liraglutide. She experienced gastrointestinal symptoms but no hypoglycemia.

The aim of this study was to compare the effect of continuation or discontinuation of glimepiride upon starting insulin therapy in type 2 diabetic patients poorly controlled with sub-maximal glimepiride.This 48-week, randomized, observational, parallel-group study consisted of a 24-week screening period and a 24-week intervention period. During the screening period, we unified the sulfonylureas to glimepiride at 3mg/day for 8 weeks, and started biphasic insulin aspart 30 (Asp30Mix) once-daily injections for 16 weeks. At the start of the intervention period, we stepped up once- to twice-daily insulin injection and randomized the 26 patients into either continuation of glimepiride group (CONT, n=14) or discontinuation of glimepiride group (DISCON, n=12). The Asp30Mix dose-adjustment algorithm was used in both groups. HbA1C, plasma glucose, insulin daily dose, body weight, and number of hypoglycaemic episodes were evaluated.At the end of the study, HbA1C improved in CONT more than in DISCON (P0.01), and daily dose of Asp30Mix was less in CONT than DISCON (P0.05). Body weight and the numbers of hypoglycaemic episodes were similar between the two groups.Continuing glimepiride (sulfonylureas) allows a better glycaemic control with less insulin daily dose compared with discontinuing glimepride.

Using a new estimated glomerular filtration rate (eGFR) equation, we undertook a retrospective chart review to investigate the clinical significance of chronic kidney disease (CKD) stage for atherosclerosis in 653 Japanese patients with type 2 diabetes that were followed from January 2004 to December 2006 at Juntendo University Hospital. Diabetic patients with CKD stage 2 or 3 detected in 2004 or before had more history of cardiovascular disease (CVD) compared with those patients without CKD [ischemic heart disease (IHD): 25% vs. 9.3%, P0.01 and stroke: 17.6% vs. 10.5%, P0.05]. In Addition, the incidence of CVD through the observation period tended to increase with progression of CKD stage (0.9% in stage 0, 3.2% in stage 1 or 2, and 3.4% in stageor =3, P=0.056), and patients with eGFR75 had a higher incidence of IHD (2.5% vs. 0.3%) and IHD or Stroke (3.3% vs. 0.7%) compared with those who had eGFRor =75. Patients with urinary albumin excretion rate (UACR)or =20mg/g Cr also had a higher incidence of IHD or stroke compared to patients with UACR20 (3.5% vs. 0.6%). In conclusion, diabetic patients with eGFR75 and/or UACRor =20 might be a high-risk population for CVD.

The aim of this study was to elucidate the effect of repetitive fluctuations in blood glucose concentrations on monocyte adhesion to the aortic endothelium. Streptozotocin induced diabetes rats were fed twice daily to induce repetitive postprandial glucose spikes. Then, we compared the number of monocytes adherent to the endothelium of thoracic aorta in these rats with that in rats fed ad libitum. In addition, we evaluated the effect of N -acetyl- l cystein and probucol which are known as antioxidants on the monocyte adhesion to endothelial cells. Streptozotocin induced diabetes rats fed twice daily showed remarkably lower HbA 1c than the rats fed ad libitum. However, the former group showed markedly higher number of monocytes adherent to the endothelium than the latter. Both N -acetyl- l cystein and probucol could not reduce the number of adherent monocytes in streptozotocin induced diabetes rats fed twice daily. Our data demonstrated that repetitive postprandial fluctuation in glucose concentration evokes monocyte adhesion to endothelial cells that was worse than that induced by stable hyperglycemia in vivo.

We previously showed that polymorphisms of the promoter area of chemokine receptor 5 (CCR5) gene (59029G/A) and its agonist, regulated upon activation, normal T-cell expressed and secreted (RANTES) gene (−28C/G) were new candidates for susceptibility to diabetic nephropathy. The aim of this study was to confirm the effect of these polymorphisms on the development and progression of diabetic nephropathy. We performed a 10-year retrospective study of 191 Japanese type 2 diabetic patients with normoalbuminuria at baseline. The subjects were classified into two groups: (1) those with persistent normoalbuminuria (group N) and (2) those with progression from normoalbuminuria to microalbuminuria or overt proteinuria (group P). Then, their association with CCR5 59029G/A and RANTES −28C/G polymorphisms was assessed. The frequency of the RANTES −28G(+) genotype did nor differ between the two groups, but the CCR5 59029A(+) genotype had a significantly higher frequency in group P than in group N (83% versus 71%, p = 0.04). By discriminant analysis, only the CCR5 59029A(+) genotype showed an independent positive correlation with the onset or progression of nephropathy ( p = 0.03, odds ratio = 2.41, 95% CI = 1.09–5.33). Therefore, the CCR5 59029A(+) genotype seems to be related the etiology of diabetic nephropathy in Japanese type 2 diabetics.

While carboxymethylated proteins are considered to be advanced glycation end products (AGE), they can also be induced by reactive oxygen species (ROS) independently of the AGE-forming process. To clarify whether N -(carboxymethyl)valine residues in hemoglobin (CMV-Hb) were a useful marker of the accumulation of ROS in diabetes, we evaluated CMV-Hb formation in vitro and in vivo. For the in vitro studying, purified human hemoglobin was incubated with d -glucose or d -glucose and hydrogen peroxide. For the in vivo study, CMV-Hb was extracted from peripheral red blood cells in diabetic patients and compared with that from non-diabetic subjects. Furthermore, the effect of antioxidants was evaluated after 6 months in 15 diabetic patients showing very high CMV-Hb levels. In vitro CMV-Hb formation increased in a glucose concentration and time-dependent manner. Co-incubation with glucose and hydrogen peroxide synergistically increased CMV-Hb formation. The CMV-Hb level was higher in the diabetic group than the non-diabetic group, and CMV-Hb was correlated with the plasma total cholesterol and serum creatinine levels. The CMV-Hb level was decreased by antioxidant therapy, whereas HbA1c did not change. These results demonstrate that CMV-Hb may be a useful marker for accumulation of oxidative stress in diabetic patients.